hc-030031 and Peripheral-Nervous-System-Diseases

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Asthma; Humans; Ion Channel Gating; Neurons; Pain; Peripheral Nervous System Diseases; Pulmonary Disease, Chronic Obstructive; Transient Receptor Potential Channels

Topics: Amides; Analgesics; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 7; Hyperalgesia; Male; Mice; Molecular Docking Simulation; Pain; Pain Measurement; Peripheral Nervous System Diseases; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Rats, Wistar; TRPA1 Cation Channel

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger α-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or α-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists.

Topics: Acetanilides; Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Purines; Pyrazines; Thioctic Acid; Transient Receptor Potential Channels; TRPA1 Cation Channel

Transient receptor potential ankyrin 1 (TRPA1) channel antagonists have suppressed mechanical hypersensitivity in peripheral neuropathy, while their effect on ongoing neuropathic pain is not yet known. Here, we assessed whether blocking the TRPA1 channel induces place-preference, an index for the relief of ongoing pain, in two experimental rat models of peripheral neuropathy. Diabetic neuropathy was induced by streptozotocin and spared nerve injury (SNI) model of neuropathy by ligation of two sciatic nerve branches. Conditioned place-preference (CPP) paradigm involved pairing of the drug treatment with one of the chambers of a CPP device once or four times, and the time spent in each chamber was recorded after conditioning sessions to reveal place-preference. The mechanical antihypersensitivity effect was assessed by the monofilament test immediately after the conditioning sessions. Intraperitoneally (30mg/kg; diabetic and SNI model) or intrathecally (10μg; diabetic model) administered Chembridge-5861528 (CHEM) was used as a selective TRPA1 channel antagonist. In diabetic and SNI models of neuropathy, CHEM failed to induce CPP at a dose that significantly attenuated mechanical hypersensitivity, independent of the route of drug administration or number of successive conditioning sessions. Intrathecal clonidine (an α2-adrenoceptor agonist; 10μg), in contrast, induced CPP in SNI but not control animals. The results indicate that ongoing pain, as revealed by CPP, is less sensitive to treatment by the TRPA1 channel antagonist than mechanical hypersensitivity in peripheral neuropathy.

Topics: Acetanilides; Adrenergic alpha-2 Receptor Agonists; Animals; Clonidine; Conditioning, Psychological; Diabetic Neuropathies; Disease Models, Animal; Hyperalgesia; Male; Neuralgia; Peripheral Nervous System Diseases; Purines; Rats; Rats, Wistar; TRPA1 Cation Channel; TRPC Cation Channels

Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1.

Topics: Acetanilides; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Cold Temperature; Drug Hypersensitivity; Glutathione; Hyperalgesia; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Paclitaxel; Peripheral Nervous System Diseases; Purines; Pyrroles; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent neurons. On the proximal nerve ending within the spinal dorsal horn, TRPA1 regulates transmission to spinal interneurons, and thereby pain hypersensitivity. Here we assessed whether the contribution of the spinal TRPA1 channel to pain hypersensitivity varies with the experimental pain model, properties of test stimulation or the behavioral pain response. The antihypersensitivity effect of intrathecally (i.t.) administered Chembridge-5861528 (CHEM; a selective TRPA1 channel antagonist; 5-10μg) was determined in various experimental models of pain hypersensitivity in the rat. In spinal nerve ligation and rapid eye movement (REM) sleep deprivation models, i.t. CHEM attenuated mechanical hypersensitivity. Capsaicin-induced secondary (central) but not primary (peripheral) mechanical hypersensitivity was also reduced by i.t. administration of CHEM or A-967079, another TRPA1 channel antagonist. Formalin-induced secondary mechanical hypersensitivity, but not spontaneous pain, was suppressed by i.t. CHEM. Moreover, mechanical hypersensitivity induced by cholekystokinin in the rostroventromedial medulla was attenuated by i.t. pretreatment with CHEM. Independent of the model, the antihypersensitivity effect induced by i.t. CHEM was predominant on responses evoked by low-intensity stimuli (⩽6g). CHEM (10μg i.t.) failed to attenuate pain behavior in healthy controls or mechanical hypersensitivities induced by i.t. administrations of a GABA(A) receptor antagonist, or NMDA or 5-HT(3) receptor agonists. Conversely, i.t. administration of a TRPA1 channel agonist, cinnamon aldehyde, induced mechanical hypersensitivity. The results indicate that the spinal TRPA1 channel exerts an important role in secondary (central) pain hypersensitivity to low-intensity mechanical stimulation in various pain hypersensitivity conditions. The spinal TRPA1 channel provides a promising target for the selective attenuation of a central mechanism contributing to pathophysiological pain.

Topics: Acetanilides; Analysis of Variance; Animals; Ankyrins; Calcium Channels; Capsaicin; Cholecystokinin; Cinnamomum zeylanicum; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hyperalgesia; Male; N-Methylaspartate; Pain Measurement; Peripheral Nervous System Diseases; Purines; Rats; Rats, Wistar; Sleep Deprivation; Spinal Cord; TRPA1 Cation Channel; TRPC Cation Channels